|Year : 2010 | Volume
| Issue : 3 | Page : 123-127
|Role of nitric oxide and its metabolites as potential markers in lung cancer
Department of Biochemistry and Microbiology, University of Kalamoon, Deratiah, Syria
|Date of Submission||03-Feb-2010|
|Date of Acceptance||24-Apr-2010|
|Date of Web Publication||2-Jul-2010|
Department of Biochemistry and Microbiology, Faculty of Pharmacy, University of Kalamoon, Deratiah
| Abstract|| |
Nitric oxide (NO) and reactive oxygen species (ROS) play important physiologic roles as mediators of signaling processes. However, high concentrations of NO and ROS result in damage to cellular and extracellular components. Excessive production of endogenous and/or exogenous ROS and NO is implicated in the pathogenesis of lung cancer. NO and its metabolites interact with ROS to generate potent nitrating agents leading to protein nitration, which is one of the several chemical modifications that occur during oxidative/nitrosative stress. Although there is considerable evidence in support of a role for NO in protein modifications and carcinogenesis, recent data suggest that NO has antagonistic cellular effects, leading to either promotion or inhibition of tumor growth. However, the role of NO in tumor biology is still poorly understood. This review demonstrates the role of NO and its metabolites as potential markers in lung cancer.
Keywords: Carcinogenesis, oxidative stress, lung cancer, nitric oxide, protein modification
|How to cite this article:|
Masri F. Role of nitric oxide and its metabolites as potential markers in lung cancer. Ann Thorac Med 2010;5:123-7
In spite of a rapid growth in the field of NO research which has attracted scientists from a variety of disciplines, and the recognition that NO may play key roles in a variety of pathologic processes including cancer, research on NO in cancer remains at its infancy. Because of the recognition that NO is a free radical, significant research has been invested into the role of NO in mutagenesis and thus, indirectly, carcinogenesis. A full understanding of the molecular biology of NO synthesis and its subsequent fate is essential in order to appreciate the roles of NO in carcinogenesis, tumor progression and cancer therapy.
| Nitric Oxide and its Biosynthesis|| |
Nitric oxide (NO) is composed of nitrogen and oxygen atoms that covalently bind to each other to form a diatomic molecule. NO is a water- and lipid-soluble gas containing an unpaired electron, making NO a highly reactive molecule that participates in many chemical reactions. NO has a short half-life (few seconds) and a short range of bioactivity. In general, NO is a relatively stable free radical that readily diffuses from the site of production, crossing cell membranes and interacting with targets without the need for special transporters or receptors. ,
The physiology of NO is complex and its role in inflammation is controversial with both anti-inflammatory and pro-inflammatory effects.  The first indication that NO played an important role in physiology was its identification as the endothelium derived relaxing factor (EDRF).  In this role, the NO that is continuously released from endothelium enters adjacent vascular smooth muscle, where it promotes vessel relaxation though its activation of soluble guanylate cyclase. Since this study, NO has been discovered to play a role in many biologic functions including cell proliferation and angiogenesis, and has also been implicated in variety of diseases such as cancer and primary arterial hypertension. ,,
NO is made from l-arginine in a reaction catalyzed by a family of intracellular enzymes called nitric oxide synthases (NOS), in the presence of oxygen and the reduced from of nicotinamide adenine dinucleotide phosphate (NADPH). This reaction requires many other cofactors including flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), calmodulin (CaM) and tetrahydrobiopterin (BH4)  [Figure 1].
| Protein Nitration: Mechanism and Selectivity|| |
Tyrosine residues in protein are susceptible to several chemical modifications including nitration, chlorination and bromination. Tyrosine residues in protein are chlorinated by HOCl to form 3-chlorotyrosine, or brominated by HOBr to form 3-bromotyrosine,  or nitrated by NO and its metabolites to form 3-nitrotyrosine (protein nitration). , Tyrosine nitration can occur when a cell or an organism experiences oxidative stress. ,
A number of pathways have been suggested for the production of 3-nitrotyrosine [Figure 2]. NO undergoes a direct bimolecular reaction with O 2− yielding peroxynitrite (ONOO−) at almost diffusion-limited rates [Figure 2], reaction A. , High levels of NO and superoxide favor the formation of peroxynitrite (reaction A). Once formed, ONOO− may nitrate tyrosine (Tyr-NO 2 ) by reaction B, or decompose to NO 3−. NO 2− may be used to nitrate proteins by a peroxidase-catalyzed reaction (reaction C).  However, the data presented to date do not confirm the existence of a single pathway but rather a multitude of biologic reactions could be responsible for the tyrosine nitration.
The process of tyrosine nitration is protein specific and alters select tyrosine residues in the affected protein. ,,,, Several factors could demonstrate this selectivity such as location of nitrating agents from the protein, abundance of the protein, number of tyrosine residues in the protein and position of tyrosine residues in a specific sequence (motif). Nitration of proteins is associated with over 50 diseases including cancer ,, and linked to many different functional consequences as apoptosis and oxidative stress.
| Role of NO in Carcinogenesis|| |
Despite the important research that has been invested into the role of NO in carcinogenesis, understanding the role of NO from initiation to promotion in a tumor remains incomplete. The effect of NO on tumors appears to depend on two main determinants: the amount of NO generated and the cell type. Excessive amounts of NO increase apoptosis in some tumor cells, whereas lower amounts can increase vascularity and protect the cells from apoptosis.  Cytotoxicity of NO varies among different cell types and in different states of differentiation. ,
Although NO has been proposed to be an important mediator of tumor growth,  the mechanism by which NO contributes to the promotion of tumor growth is still unclear. The involvement of NO in cancer is complex, leading to either promotion or inhibition of tumor growth.  Some studies have shown that presence of NO dramatically reduced aggressiveness of the tumor, whereas others have reported that tumor cell lines became more aggressive. , Currently, it is believed that high levels of NO may be cytostatic or cytotoxic for tumor cells, whereas low levels may promote tumor growth , ; however, the role of NO in tumor biology is still poorly understood.
| Effect of NO and its Metabolites in Lung Cancer|| |
The effort to reduce lung cancer mortality over the last 30 years has been the most evident and costly failure in the war on cancer. Lung cancer is the most common cause of cancer death. Lung cancer accounts for 28% of cancer deaths and about 6% of all deaths. Lung cancer can be initiated when a normal cell within the lung undergoes genetic mutations, causing it to become an abnormal cell. These abnormal cells can form a tumor that has the potential to invade neighboring blood vessels and it spreads to other places in the lungs.
Tobacco smoke is the main cause for lung cancer and is responsible for 87% of all lung cancers in the United States. , The risk increases with the amount of tobacco used and the amount of time it has been used. Cigarette smoke, a major source of exogenous oxidants, leads to chronic airway inflammation with accumulation and activation of leukocytes which produce high levels of reactive oxygen species (ROS) and NO. For example, cigarette smoke contains 10 14 ROS ,, and 700 ppm NO per puff. , Excessive or inappropriate production of endogenous and/or exogenous ROS and NO is implicated in the pathogenesis of lung cancer. , High levels of oxidative stress have been noticed in patients with advanced lung cancer.  Masri et al, showed that lung cancer patients have increased exhaled NO compared to healthy controls.  Exhaled NO levels were measured by an off-line method according to the established guidelines by American Thoracic Society using a chemiluminescent analyzer (NOA 280, Sievers, Boulder, CO, USA). 
Recently, breath analysis, which includes gaseous phase analysis that measures exhaled nitric oxide, and exhaled breath condensate (EBC), has been proposed as a noninvasive and simple technique to investigate neoplastic processes in the airways and for the early detection of lung cancer. 
Nitric oxide by itself is relatively nonreactive.  Its damaging properties are derived from its reaction with ROS which may modify protein function through nitration ,, or cause nucleotide modifications in DNA , and thus are potentially carcinogenic in the long term [Figure 3]. Lung cancer patients have significantly higher levels of nitrated proteins in serum, supporting the presence of oxidative and nitrosative stress. , Immunohistochemistry studies have shown that protein nitration is increased in the tumor relative to the tumor-free region in lung cancer patients. The presence of nitrotyrosine appears tightly defined to the boundaries of the tumors [Figure 4].  Protein nitration is typically considered to be a marker of oxidative damage rather than as an active agent responsible for pathogenic effects. ,,,19] Protein nitration is a specific process affecting select proteins in cells and tissues. ,,,
NO and protein nitration may have combined effects on tumorigenesis. NO consumptive mechanisms require oxygen. In the hypoxic environment of the tumor, NO consumption may decrease leading to local increases of NO. Thomas et al, have shown that levels of NO determine its biologic effects including angiogenesis, erythropoiesis and glycolysis.  At low levels of NO, activation of HIF-1a occurs; but at higher levels, NO inactivates p53, a tumor suppressor that regulates cell cycle genes such as p21 waf/cip1. , Over 90% of lung tumors are defective in p53, but p53 inactivation by nitration could also contribute to carcinogenesis. Other proteins previously associated with lung cancer such as hnRNPK are also nitrated and they may significantly enhance cell proliferation and anchorage-independent growth.  Likewise, nitration of annexin III may affect cell growth and signaling pathways.  With broad effects on angiogenesis, glycolysis, p53 activity, antioxidant potential in the lung and alterations in cell growth pathways, NO may create a microenvironment that can initiate tumorigenesis and/or promote tumor heterogeneity leading to metastasis.
| Role of NO and Exhaled Breath in Diagnosing and Monitoring Lung Cancer|| |
Although recent studies show increased level of exhaled nitric oxide (ENO) and its metabolites including protein nitration in lung carcinogenesis, the evaluation of such changes in level of nitration as a potential marker for lung cancer is poorly researched, especially its clinical aspects.
Currently, measurement of ENO has evinced a lot of interest in the diagnosis, treatment and monitoring of asthma. Concentration of exhaled nitric oxide is markedly elevated in asthma, and its elevation is positively related to the degree of eosinophilic airway inflammation and symptoms. ,, We believe that ENO and nitrated proteins can also be used as potential clinical markers in lung cancer if further investigations are done.
Some studies listed a number of proteins that were nitrated in cancer including lung cancer. ,,, It is known that nitration of some of these proteins, e.g., aldolase and manganese superoxide dismutase (MnSOD), causes loss of their activities.  Determination of these target proteins may allow other researchers in the cancer field to evaluate them as potential disease markers and to determine novel pathways that may be involved in carcinogenesis.
Recently, there has been a sudden increase in the number of studies investigating the biomarkers of lung cancer in exhaled breath, using the induced sputum technique which allows sampling of the airways in a noninvasive manner. Published data have shown that exhaled breath contains a pattern of volatile organic compounds (VOCs), which distinguishes patients with and without lung cancer. , Lately, a simpler method of detecting unique patterns of VOCs has been developed using gaseous chemical sensing devices. Mazzone et al, showed by using a colorimetric sensor array that patients with lung cancer present a unique chemical signature of the breath with moderate accuracy.  Recent advances in odor-sensing technology have created chemical sensing devices called "electronic noses". Electronic noses rely on arrays of chemical vapor sensors that respond to specific stereochemical characteristics of an odorant molecule, particularly VOCs.  Machado et al, showed that the exhaled breath of patients with lung cancer has distinct characteristics that can be identified with an electronic nose.  Further, EBC also contains biomarkers of oxidative stress, which is an imbalance between oxidants and antioxidants, associated with lung cancer development. 
Although different exhaled biomarkers have been studied in lung cancer patients, further validation studies are required before using them.
It is hoped that this information will encourage and assist government and non-government service providers to do clinical studies in order for exhaled breath analysis including NO measurement to become fully established in the diagnosis and management of lung cancer.
| Conclusion|| |
The prognosis of lung cancer is still poor because of the absence of valid approaches to its early detection. Exhaled breath analysis and ENO measurement may provide useful assays in predicting diagnosis and disease progression.
This review lays the groundwork for future studies to address the role of NO and protein nitration in carcinogenesis. Since the levels of NO are higher in cancer patients and nitration is restricted to the tumor, these suggest novel roles of these mechanisms in the tumor. Further work is required to determine the functional consequences of protein tyrosine nitration and its clinical role in the disease process.
| Acknowledgments|| |
The author is indebted to Dr. Serpil Erzurum and Dr. Aulak Kulwant for their efforts in reading the article and providing valuable comments on this review.
| References|| |
|1.||Behrend L, Henderson G, Zwacka RM. Reactive oxygen species in oncogenic transformation. Biochem Soc Trans 2003;31:1441-4. [PUBMED] [FULLTEXT] |
|2.||Marletta MA. Nitric oxide: Biosynthesis and biological significance. Trends Biochem Sci 1989;14:488-92. [PUBMED] |
|3.||Ischiropoulos H. Biological tyrosine nitration: A pathophysiological function of nitric oxide and reactive oxygen species. Arch Biochem Biophys 1998;356:1-11. [PUBMED] [FULLTEXT] |
|4.||Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res 1987;61:866-79. [PUBMED] [FULLTEXT] |
|5.||Kiyosawa H, Suko M, Okudaira H, Murata K, Miyamoto T, Chung MH, et al. Cigarette smoking induces formation of 8-hydroxydeoxyguanosine, one of the oxidative DNA damages in human peripheral leukocytes. Free Radic Res Commun 1990;11:23-7. [PUBMED] |
|6.||Wiseman H, Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: Role in inflammatory disease and progression to cancer. Biochem J 1996;313:17-29. [PUBMED] [FULLTEXT] |
|7.||Harris CC. p53 tumor suppressor gene: At the crossroads of molecular carcinogenesis, molecular epidemiology, and cancer risk assessment. Environ Health Perspect 1996;104:435-9. [PUBMED] [FULLTEXT] |
|8.||Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002-12. [PUBMED] [FULLTEXT] |
|9.||Aldridge RE, Chan T, van Dalen CJ, Senthilmohan R, Winn M, Venge P, et al. Eosinophil peroxidase produces hypobromous acid in the airways of stable asthmatics. Free Radic Biol Med 2002;33:847-56. [PUBMED] [FULLTEXT] |
|10.||Beckman JS, Ischiropoulos H, Zhu L, van der Woerd M, Smith C, Chen J, et al. Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite. Arch Biochem Biophys 1992;298:438-45. [PUBMED] |
|11.||Haddad IY, Pataki G, Hu P, Galliani C, Beckman JS, Matalon S. Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury. J Clin Invest 1994;94:2407-13. [PUBMED] [FULLTEXT] |
|12.||MacMillan-Crow LA, Crow JP, Kerby JD, Beckman JS, Thompson JA. Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts. Proc Natl Acad Sci U S A 1996;93:11853-8. [PUBMED] [FULLTEXT] |
|13.||Rochelle LG, Fischer BM, Adler KB. Concurrent production of reactive oxygen and nitrogen species by airway epithelial cells in vitro. Free Radic Biol Med 1998;24:863-8. [PUBMED] [FULLTEXT] |
|14.||Gow AJ, Farkouh CR, Munson DA, Posencheg MA, Ischiropoulos H. Biological significance of nitric oxide-mediated protein modifications. Am J Physiol Lung Cell Mol Physiol 2004;287:L262-8. [PUBMED] [FULLTEXT] |
|15.||Wu W, Samoszuk MK, Comhair SA, Thomassen MJ, Farver CF, Dweik RA, et al. Eosinophils generate brominating oxidants in allergen-induced asthma. J Clin Invest 2000;105:1455-63. [PUBMED] [FULLTEXT] |
|16.||Wattanapitayakul SK, Weinstein DM, Holycross BJ, Bauer JA. Endothelial dysfunction and peroxynitrite formation are early events in angiotensin-induced cardiovascular disorders. Faseb J 2000;14:271-8. [PUBMED] [FULLTEXT] |
|17.||Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 2000;87:241-7. [PUBMED] [FULLTEXT] |
|18.||Oyama J, Shimokawa H, Momii H, Cheng X, Fukuyama N, Arai Y, et al. Role of nitric oxide and peroxynitrite in the cytokine-induced sustained myocardial dysfunction in dogs in vivo. J Clin Invest 1998;101:2207-14. [PUBMED] [FULLTEXT] |
|19.||Kondo S, Toyokuni S, Tsuruyama T, Ozeki M, Tachibana T, Echizenya M, et al. Peroxynitrite-mediated stress is associated with proliferation of human metastatic colorectal carcinoma in the liver. Cancer Lett 2002;179:87-93. [PUBMED] [FULLTEXT] |
|20.||Aulak KS, Miyagi M, Yan L, West KA, Massillon D, Crabb JW, et al. Proteomic method identifies proteins nitrated in vivo during inflammatory challenge. Proc Natl Acad Sci U S A 2001;98:12056-61. [PUBMED] [FULLTEXT] |
|21.||Ara J, Przedborski S, Naini AB, Jackson-Lewis V, Trifiletti RR, Horwitz J, et al. Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Proc Natl Acad Sci U S A 1998;95:7659-63. [PUBMED] [FULLTEXT] |
|22.||Gow A, Duran D, Thom SR, Ischiropoulos H. Carbon dioxide enhancement of peroxynitrite-mediated protein tyrosine nitration. Arch Biochem Biophys 1996;333:42-8. [PUBMED] [FULLTEXT] |
|23.||Wink DA, Mitchell JB. Nitric oxide and cancer: An introduction. Free Radic Biol Med 2003;34:951-4. [PUBMED] [FULLTEXT] |
|24.||Shi Q, Xiong Q, Wang B, Le X, Khan NA, Xie K. Influence of nitric oxide synthase II gene disruption on tumor growth and metastasis. Cancer Res 2000;60:2579-83. [PUBMED] [FULLTEXT] |
|25.||Mackenzie-Graham AJ, Mitrovic B, Smoll A, Merrill JE. Differential sensitivity to nitric oxide in immortalized, cloned murine oligodendrocyte cell lines. Dev Neurosci 1994;16:162-71. [PUBMED] |
|26.||Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW, Mitchell JB. The multifaceted roles of nitric oxide in cancer. Carcinogenesis 1998;19:711-21. [PUBMED] [FULLTEXT] |
|27.||Xie K, Huang S. Contribution of nitric oxide-mediated apoptosis to cancer metastasis inefficiency. Free Radic Biol Med 2003;34:969-86. [PUBMED] [FULLTEXT] |
|28.||Jenkins DC, Charles IG, Thomsen LL, Moss DW, Holmes LS, Baylis SA, et al. Roles of nitric oxide in tumor growth. Proc Natl Acad Sci U S A 1995;92:4392-6. [PUBMED] [FULLTEXT] |
|29.||Mulshine JL, Cuttitta F, Tockman MS, De Luca LM. Lung cancer evolution to preinvasive management. Clin Chest Med 2002;23:37-48. [PUBMED] |
|30.||Bilello KS, Murin S, Matthay RA. Epidemiology, etiology, and prevention of lung cancer. Clin Chest Med 2002;23:1-25. [PUBMED] |
|31.||Church DF, Pryor WA. Free-radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect 1985;64:111-26. [PUBMED] [FULLTEXT] |
|32.||Zang LY, Stone K, Pryor WA. Detection of free radicals in aqueous extracts of cigarette tar by electron spin resonance. Free Radic Biol Med 1995;19:161-7. [PUBMED] [FULLTEXT] |
|33.||Rahman I, MacNee W. Role of oxidants/antioxidants in smoking-induced lung diseases. Free Radic Biol Med 1996;21:669-81. [PUBMED] [FULLTEXT] |
|34.||Flicker TM, Green SA. Comparison of gas-phase free-radical populations in tobacco smoke and model systems by HPLC. Environ Health Perspect 2001;109:765-71. [PUBMED] [FULLTEXT] |
|35.||Last JA, Sun WM, Witschi H. Ozone, NO, and NO 2 : Oxidant air pollutants and more. Environ Health Perspect 1994;102:179-84. [PUBMED] [FULLTEXT] |
|36.||Esme H, Cemek M, Sezer M, Saglam H, Demir A, Melek H, et al. High levels of oxidative stress in patients with advanced lung cancer. Respirology 2008;13:112-6. [PUBMED] |
|37.||Masri FA, Comhair SA, Koeck T, Xu W, Janocha A, Ghosh S, et al. Abnormalities in nitric oxide and its derivatives in lung cancer. Am J Respir Crit Care Med 2005;172:597-605. [PUBMED] [FULLTEXT] |
|38.||Dweik RA, Laskowski D, Ozkan M, Farver C, Erzurum SC. High levels of exhaled nitric oxide (NO) and NO synthase III expression in lesional smooth muscle in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2001;24:414-8. [PUBMED] [FULLTEXT] |
|39.||Chan HP, Lewis C, Thomas PS. Exhaled breath analysis: Novel approach for early detection of lung cancer. Lung Cancer 2009;63:164-8. [PUBMED] [FULLTEXT] |
|40.||Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and ugly. Am J Physiol 1996;271:C1424-37. [PUBMED] [FULLTEXT] |
|41.||van der Vliet A, O'Neill CA, Halliwell B, Cross CE, Kaur H. Aromatic hydroxylation and nitration of phenylalanine and tyrosine by peroxynitrite: Evidence for hydroxyl radical production from peroxynitrite. FEBS Lett 1994;339:89-92. [PUBMED] [FULLTEXT] |
|42.||Ohshima H, Friesen M, Brouet I, Bartsch H. Nitrotyrosine as a new marker for endogenous nitrosation and nitration of proteins. Food Chem Toxicol 1990;28:647-52. [PUBMED] |
|43.||Szabo C, Ohshima H. DNA damage induced by peroxynitrite: Subsequent biological effects. Nitric Oxide 1997;1:373-85. |
|44.||Gole MD, Souza JM, Choi I, Hertkorn C, Malcolm S, Foust RF 3rd, et al. Plasma proteins modified by tyrosine nitration in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2000;278:L961-7. [PUBMED] [FULLTEXT] |
|45.||Pignatelli B, Li CQ, Boffetta P, Chen Q, Ahrens W, Nyberg F, et al. Nitrated and oxidized plasma proteins in smokers and lung cancer patients. Cancer Res 2001;61:778-84. [PUBMED] [FULLTEXT] |
|46.||Thomas DD, Espey MG, Vitek MP, Miranda KM, Wink DA. Protein nitration is mediated by heme and free metals through Fenton-type chemistry: An alternative to the NO/O 2 - reaction. Proc Natl Acad Sci U S A 2002;99:12691-6. [PUBMED] [FULLTEXT] |
|47.||Cobbs CS, Whisenhunt TR, Wesemann DR, Harkins LE, Van Meir EG, Samanta M. Inactivation of wild-type p53 protein function by reactive oxygen and nitrogen species in malignant glioma cells. Cancer Res 2003;63:8670-3. [PUBMED] [FULLTEXT] |
|48.||Chazotte-Aubert L, Hainaut P, Ohshima H. Nitric oxide nitrates tyrosine residues of tumor-suppressor p53 protein in MCF-7 cells. Biochem Biophys Res Commun 2000;267:609-13. [PUBMED] [FULLTEXT] |
|49.||Pino I, Pνo R, Toledo G, Zabalegui N, Vicent S, Rey N, et al. Altered patterns of expression of members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family in lung cancer. Lung Cancer 2003;41:131-43. |
|50.||Bastian BC. Annexins in cancer and autoimmune diseases. Cell Mol Life Sci 1997;53:554-6. [PUBMED] [FULLTEXT] |
|51.||Strunk RC, Szefler SJ, Phillips BR, Zeiger RS, Chinchilli VM, Larsen G, et al. Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children. J Allergy Clin Immunol 2003;112:883-92. [PUBMED] [FULLTEXT] |
|52.||Lim KG, Mottram C. The use of fraction of exhaled nitric oxide in pulmonary practice. Chest 2008;133:1232-42. [PUBMED] [FULLTEXT] |
|53.||Dupont LJ, Demedts MG, Verleden GM. Prospective evaluation of the validity of exhaled nitric oxide for the diagnosis of asthma. Chest 2003;123:751-6. [PUBMED] [FULLTEXT] |
|54.||Liu CY, Wang CH, Chen TC, Lin HC, Yu CT, Kuo HP. Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer. Br J Cancer 1998;78:534-41. [PUBMED] [FULLTEXT] |
|55.||Aulak KS, Koeck T, Crabb JW, Stuehr DJ. Dynamics of protein nitration in cells and mitochondria. Am J Physiol Heart Circ Physiol 2004;286:H30-8. [PUBMED] [FULLTEXT] |
|56.||Phillips M, Gleeson K, Hughes JM, Greenberg J, Cataneo RN, Baker L, et al. Volatile organic compounds in breath as markers of lung cancer: A cross-sectional study. Lancet 1999;353:1930-3. [PUBMED] [FULLTEXT] |
|57.||Poli D, Carbognani P, Corradi M, Goldoni M, Acampa O, Balbi B, et al. Exhaled volatile organic compounds in patients with non-small cell lung cancer: Cross sectional and nested short-term follow-up study. Respir Res 2005;6:71. [PUBMED] [FULLTEXT] |
|58.||Mazzone PJ, Hammel J, Dweik R, Na J, Czich C, Laskowski D, et al. Diagnosis of lung cancer by the analysis of exhaled breath with a colorimetric sensor array. Thorax 2007;62:565-8. [PUBMED] [FULLTEXT] |
|59.||Munoz BC, Steinthal G, Sunshine S. Conductive polymer- carbon black composites-based sensor arrays for use in a electronic nose. Sensor Rev 1999;19:300-5. |
|60.||Machado RF, Laskowski D, Deffenderfer O, Burch T, Zheng S, Mazzone PJ, et al. Detection of lung cancer by sensor array analyses of exhaled breath. Am J Respir Crit Care Med 2005;171:1286-91. [PUBMED] [FULLTEXT] |
|61.||Møller P, Folkmann JK, Forchhammer L, Bräuner EV, Danielsen PH, Risom L, et al. Air pollution, oxidative damage to DNA, and carcinogenesis. Cancer Lett 2008;266:84-97. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
|This article has been cited by|
||Measurement of exhaled alveolar nitrogen oxide in patients with lung cancer: A friend from the past still precious today
| ||Kallianos, A. and Tsimpoukis, S. and Zarogoulidis, P. and Darwiche, K. and Charpidou, A. and Tsioulis, I. and Trakada, G. and Porpodis, K. and Spyratos, D. and Panoutsopoulos, A. and Veletza, L. and Kostopoulos, K. and Kostopoulos, C. and Karapantzos, I. and Tsakiridis, K. and Hohenforst-Schmidt, W. and Zarogoulidis, K. and Rapti, A. and Syrigos, K. |
| ||OncoTargets and Therapy. 2013; 6: 609-613 |
||Nitric oxide and cancer: A review
| ||Korde Choudhari, S. and Chaudhary, M. and Bagde, S. and Gadbail, A.R. and Joshi, V. |
| ||World Journal of Surgical Oncology. 2013; 11(118) |
||Detection of reactive oxygen metabolites in malignant and adjacent normal tissues of patients with lung cancer
| ||Okur, H.K. and Yuksel, M. and Lacin, T. and Baysungur, V. and Okur, E. |
| ||World Journal of Surgical Oncology. 2013; 11(9) |
||Cyclin D1 polymorphism in non-small cell lung cancer in a Portuguese population
| ||Catarino, R. and Coelho, A. and Nogueira, A. and Ara├║jo, A. and Gomes, M. and Lopes, C. and Medeiros, R. |
| ||Cancer Biomarkers. 2012; 12(2): 65-72 |
||Effect of exposure to volatile organic compounds (VOCs) on airway inflammatory response in mice
| ||Wang, F. and Li, C. and Liu, W. and Jin, Y. |
| ||Journal of Toxicological Sciences. 2012; 37(4): 739-748 |
||Nasal nitric oxide and lifestyle exposure to tobacco smoke
| || Zhou, H., Zou, B., Hazucha, M., Carson, J.L. |
| || Annals of Otology, Rhinology and Laryngology. 2011; 120(7): 455-459 |
| Article Access Statistics|
| Viewed||6556 |
| Printed||220 |
| Emailed||3 |
| PDF Downloaded||837 |
| Comments ||[Add] |
| Cited by others ||6 |